Identification of the components, targets, and magnitude of an effective immune response to HIV are important steps toward the development of an effective vaccine. Although patients with normal CD4+ T cell counts and low levels of plasma virus are a heterogeneous group, a small subgroup of patients with truly non-progressive HIV infection and restriction of virus replication likely hold important clues to the basis of an effective immune response to HIV. For this reason we have focused considerable attention on groups of such patients who are felt to have immune system mediated restriction of virus replication. It now appears clear that a large fraction of patients previously considered long term non-progressors (LTNPs) ultimately show a decline of CD4+ T cell numbers. A small subpopulation (fewer than 0.8% of HIV infected individuals) shows no signs of progression over a 10 year period. We have assembled a unique cohort of such patients with non-progressive disease. Many of these patients have been infected for 13 years with no CD4+ T cell decline, plasma virus below the levels of detection, and no virus cultured in routine CD8+ T cell depleted cultures. Cells from these patients, all of whom are untreated, are being used to systematically dissect the mechanisms of immune mediated restriction of virus replication. Studies of the HIV specific immune responses of LTNPs have provided only correlative data. Development of an in vivo model permits more direct evidence of immune mediated restriction of virus replication. Recently we established a small animal (SCID-hu- HIV/PBMC) model which uses mice that are immunodeficient such that they are able to accept a graft of peripheral blood mononuclear cells (PBMC) of infected patients. In this small subgroup of non-progressors, we were able to demonstrate a novel phenotype of lack of endogenous virus replication and CD8+ T cell mediated resistance to HIV challenge in this animal model. This resistance was associated with a strong CD4+ T cell proliferative response to HIV antigens in vitro. In these LTNP patients 0.2-0.8% of circulating CD4+ T cells were found to be specific for HIV. Surprisingly, similar numbers of HIV specific cells were found in some patients with slowly progressive disease lacking a proliferative response to HIV antigens. This indicates that HIV specific cells are retained in some patients that do not exhibit a proliferative response in vitro and raises the possibility of restimulating CD4+ T cells in such patients. We have also characterized the CD8+ T cell responses of LTNP patients. Between 0.8-18% of circulating CD8+ T cells are specific for HIV. Induction of responses of this magnitude is likely an important goal of vaccines for HIV based in CD8+ T cell mediated immunity. - HIV immunity; long term non- progressors;SCID-Hu mouse;proliferative response;cytotoxic T cell; HIV vaccine;intracellular cytokine - Human Subjects & Human Subjects: Interview, Questionaires, or Surveys Only